Platelet Inhibition With Cangrelor and Crushed Ticagrelor in Patients With ST-Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Results of the CANTIC Study
VIEW EDITORIAL:Cangrelor for ST-Segment–Elevation Myocardial Infarction
Abstract
Background:
The platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention (P-PCI). In turn, this leads to a gap in platelet inhibition, exposing patients to an increased risk of early thrombotic complications and underscoring the need to define strategies associated with more effective platelet inhibition in the peri–primary percutaneous coronary intervention period. Cangrelor is an intravenous P2Y12 inhibitor with prompt and potent antiplatelet effects. However, to date, there are limited data on the effects of cangrelor used in combination with ticagrelor in patients undergoing primary percutaneous coronary intervention. Moreover, questions have emerged on the potential for drug–drug interactions during the transition from cangrelor to oral P2Y12 inhibitors.
Methods:
This was a prospective, randomized, double-blind, placebo-controlled pharmacodynamic study conducted in patients undergoing primary percutaneous coronary intervention (n=50) who were randomized to treatment with either cangrelor or matching placebo (bolus followed by 2-hour infusion). All patients received ticagrelor 180-mg loading dose administered as crushed tablets at the time of cangrelor/placebo bolus administration. Pharmacodynamic analyses were performed at 8 time points. Pharmacodynamic effects were measured as P2Y12 reaction units by VerifyNow and platelet reactivity index by vasodilator-stimulated phosphoprotein.
Results:
Compared with placebo, cangrelor was associated with reduced P2Y12 reaction units as early as 5 minutes after bolus, which persisted during the entire duration of drug infusion, including at 30 minutes (63 [32–93] versus 214 [183–245]; mean difference, 152 [95% CI, 108–195]; P<0·001; primary end point). Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with cangrelor. After discontinuation of cangrelor/placebo infusion, there were no differences in levels of platelet reactivity between groups, ruling out a drug–drug interaction when cangrelor and ticagrelor are concomitantly administered.
Conclusions:
In patients undergoing primary percutaneous coronary intervention, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y12 inhibition induced by ticagrelor. Ticagrelor can be administered as a crushed formulation concomitantly with cangrelor without any apparent drug–drug interaction. The clinical implications of these pharmacodynamic findings warrant investigation in an adequately powered clinical trial.
Clinical Trial Registration:
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03247738
Clinical Perspective
What Is New?
•
CANTIC (Platelet Inhibition With Cangrelor and Crushed Ticagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention) showed that the addition of cangrelor leads to prompter and more potent platelet inhibitory effects compared with crushed ticagrelor alone in patients undergoing primary percutaneous coronary intervention.
•
Significant differences were observed as early as 5 minutes after bolus administration and persisted until the end of its 2-hour infusion.
•
CANTIC is the first study designed in patients undergoing primary percutaneous coronary intervention to rule out a drug–drug interaction when cangrelor and ticagrelor are concomitantly administered.
What Are the Clinical Implications?
•
CANTIC is the first study to demonstrate that cangrelor is able to bridge the gap in platelet inhibition compared with crushed oral P2Y12 inhibitors, the fastest oral formulations of P2Y12 inhibitors.
•
Although our study was not powered for clinical outcomes, high on-treatment platelet reactivity rates, a surrogate marker of thrombotic complications, were markedly decreased and make CANTIC results the best available evidence on the efficacy of cangrelor in primary percutaneous coronary intervention.
•
The lack of drug–drug interaction observed has important implications for clinical practice because it allows a more versatile use of ticagrelor with respect to timing of its administration in patients treated with cangrelor.
Introduction
Editorial, see p 1671
Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment for the prevention of thrombotic events in patients with ST-segment–elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (P-PCI).1 The new-generation oral P2Y12 inhibitors (ie, prasugrel and ticagrelor) are characterized by potent platelet inhibitory effects and are recommended over clopidogrel in P-PCI.2 However, in patients undergoing P-PCI, the onset of action of oral P2Y12 inhibitors, including prasugrel and ticagrelor, is delayed. They require several hours to achieve their full antiplatelet effects, thereby increasing the risk of early thrombotic complications.3,4 These pharmacodynamic (PD) observations underscore the need to define strategies associated with prompter, more effective platelet inhibition in the peri–percutaneous coronary intervention (PCI) period in patients with STEMI. The use of high–loading-dose (LD) regimens of oral P2Y12 inhibitors has shown to be largely ineffective in achieving faster PD effects in patients undergoing P-PCI.5,6 On the contrary, crushing tablets of oral P2Y12 inhibitors accelerates their onset of action and time to achieve full antiplatelet effects.7,8
The need for gastrointestinal absorption inevitably is a limiting step for orally administered drugs to exert their effects, suggesting the need for parenteral therapies to achieve prompt platelet inhibition.1 Cangrelor is an intravenous P2Y12 inhibitor that has been shown to reduce thrombotic complications in P2Y12 inhibitor–naïve patients undergoing PCI.9–11 However, cangrelor was tested against clopidogrel, which has delayed and modest antiplatelet effects compared with the new-generation P2Y12 inhibitors.9–11 How cangrelor compares with a crushed oral P2Y12 inhibitor, the fastest-acting formulation available, in patients undergoing P-PCI is unknown. Moreover, questions have emerged about the potential for drug–drug interactions (DDIs) during the transition from cangrelor to oral P2Y12 inhibitors.12,13 Although a DDI has not been shown during the transition from cangrelor to ticagrelor, the data to support this derive from a small low-risk patient cohort not in the setting of PCI and from nonrandomized, single-center observational series.14,15 Overall, these observations set the rationale for conducting this PD investigation comparing cangrelor with placebo in patients undergoing P-PCI concomitantly treated with crushed ticagrelor.
Methods
Study Design and Participants
The CANTIC study (Platelet Inhibition With Cangrelor and Crushed Ticagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention) was a prospective, randomized, double-blind, placebo-controlled, parallel-design investigation aimed to assess the PD effects of cangrelor versus placebo in patients undergoing P-PCI concomitantly treated with crushed ticagrelor (https://www.clinicaltrials.gov, NCT03247738). This was a single-center study conducted at the University of Florida Health–Jacksonville. P2Y12 receptor inhibitor–naïve patients presenting with an STEMI with intent to undergo P-PCI were screened for study eligibility (the online-only Data Supplement lists specific study inclusion and exclusion criteria). The study complied with the Declaration of Helsinki and was approved by the Western Institutional Review Board, and all patients gave their written informed consent. The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.
Randomization, Masking, and Study Procedures
After diagnostic angiography and confirmation of the need to proceed with P-PCI, with the use of a computer-based randomization system, patients were randomly assigned 1:1 to receive either cangrelor (30-μg/kg bolus followed by 4–μg·kg−1·min−1 infusion) or matching placebo (normal saline bolus and infusion). Masking was performed by our institutional research pharmacy. Cangrelor infusion was maintained for 2 hours. A 180-mg LD of crushed ticagrelor was administered simultaneously with the bolus administration of either cangrelor or matching placebo. The 180-mg LD of ticagrelor consisted of 2 ticagrelor 90-mg tablets that were crushed with a commercially available syringe crusher, as previously described.8 Study medications were administered in the cardiac catheterization laboratory after diagnostic angiography and before the guide wire was passed through the target lesion (the online-only Data Supplement provides details of medication blinding procedures and crushing of ticagrelor tablets).
All patients were treated as per local standard of care, which included 325 mg aspirin and 4000 IU unfractionated heparin at the time of presentation. The choice of intravenous anticoagulant during P-PCI (unfractionated heparin or bivalirudin) was at the discretion of the treating physician. Patients with planned use of glycoprotein IIb/IIIa inhibitors (GPIs) were excluded because of their interference with the VerifyNow assay; bailout GPI use was allowed at the discretion of the treating operator. The P-PCI procedure was performed as per local practice standards, including the route of access (femoral versus radial), use of an aspiration device, and stent type. All patients received fentanyl at the time of P-PCI as per local standard of care. After PCI, all patients were prescribed aspirin 81 mg/d indefinitely and ticagrelor 90 mg twice daily for at least 12 months.
PD Assessments
Platelet reactivity was measured with 2 different assays: VerifyNow P2Y12 point-of-care testing (Accriva, San Diego, CA) and vasodilator-stimulated phosphoprotein (the online-only Data Supplement provides details on PD assays). In brief, VerifyNow P2Y12 point-of-care testing measures platelet aggregation after treatment with P2Y12 inhibitors as an increase in light transmittance and reports results in P2Y12 reaction units (PRU).6,8,10 Vasodilator-stimulated phosphoprotein is a marker of P2Y12 receptor reactivity (Biocytex Inc, Marseille, France) and quantified by the platelet reactivity index (PRI).16 High on-treatment platelet reactivity (HPR) was defined in line with expert consensus definitions as PRU >208 or PRI >50%.17
PD assessments were performed at the following 8 time points: baseline (before LD administration); 5 minutes, 30 minutes, 1 hour, and 2 hours after cangrelor/placebo bolus; at the end of PCI (defined as when the guiding catheter was removed); and 1 and 2 hours after the cangrelor/placebo infusion was stopped. A flow diagram of the study is shown in Figure 1.
Outcomes and Sample Size Calculation
The primary end point of our study was the comparison of platelet reactivity measured by VerifyNow PRU between cangrelor plus crushed ticagrelor and placebo plus crushed ticagrelor at 30 minutes after drugs were administered at the start of PCI. We hypothesized that cangrelor would significantly reduce PRU. Assuming a common SD of 70 PRU, a sample size of 20 patients per group would allow detection of a 70-PRU difference between groups with 85% power and a 2-sided α of 0.05. Considering the 2 arms and a possible 25% rate of invalid PD results because of hemolysis, technical problems, or dropout, we planned to randomize up to 50 patients in order to have complete data for the primary end-point analysis. Our sample size was based on data derived from previously published studies.9,10,18 Secondary objectives included the comparison of PRU between cangrelor and placebo at other time points, the comparison of PRI at all time points, and the comparison of HPR rates between cangrelor and placebo at all time points.
Statistical Analysis
Categorical variables are expressed as frequencies and percentages. Continuous variables are presented as mean±SD or median (interquartile range). Comparisons between categorical variables were performed with a 2-tailed Fisher exact test or the Pearson χ2 test. Continuous variables were analyzed for normal distribution with the Kolmogorov-Smirnov test. For baseline characteristics, the Student t test and Mann-Whitney Utest were used to compare continuous variables when appropriate. For PD data, an ANCOVA method with a general linear model, with the baseline value of platelet reactivity used as a covariate, was used to evaluate the primary end point and all between-group comparisons in platelet reactivity. A linear mixed-effects model with treatment group, time, and treatment group by time as fixed effects and patient as a random effect was used to evaluate the overall difference between groups over time and within-group comparisons. Given the exploratory nature of the analysis and in line with previously published studies, adjustment for multiple comparisons was not performed.8 Missing data (eg, resulting from hemolyzed blood samples, inability to draw blood, or dropouts) were not imputed. PD data are reported as least-square mean and 95% CIs. A value of P<0.05 was considered statistically significant. Statistical analysis was performed with SPSS version 24.0 software (SPSS Inc, Chicago, IL).
The safety population was composed of all patients exposed to at least 1 dose of study medication (any time from randomization until completion of the study). Any adverse event until time of discharge was recorded. The PD population included all patients with PD data and without a major protocol deviation thought to affect the PD effects of ticagrelor or cangrelor. The PD population was used for analysis of all primary and secondary PD variables. Erroneously treated patients (eg, those randomized to 1 treatment but actually given the other) were accounted for on the basis of the actual treatment received. In patients receiving bailout GPI after the time at which the primary end point was assessed (30 minutes), VerifyNow samples were no longer collected after GPI administration, but vasodilator-stimulated phosphoprotein data were analyzed.
The first and corresponding authors had full access to all data in the study and take responsibility for their integrity and the data analysis.
Results
Patient Population
Between December 10, 2017, and July 17, 2018, a total of 99 patients with STEMI with intent to undergo P-PCI presented to our institution, of whom 69 provided their written informed consent to participate in the study. Of these, 50 patients were randomized (cangrelor plus crushed ticagrelor, n=25; placebo plus crushed ticagrelor, n=25) and received study medication, representing the safety population. A total of 44 patients (cangrelor plus crushed ticagrelor, n=22; placebo plus crushed ticagrelor, n=22) met the criteria to be included in the PD population. Patient disposition is summarized in Figure 2. Clinical and procedural characteristics are summarized in the Table. The 2 groups were well balanced, with the exception of a numerically higher prevalence of patients requiring bailout GPI use in the placebo arm (20% versus 4%; P=0.082). One patient in the placebo arm experienced an acute definite stent thrombosis 30 minutes after PCI and underwent emergent revascularization. During hospitalization, 2 patients experienced cardiogenic shock, resulting in death at 24 and 72 hours after P-PCI in the placebo and cangrelor arm, respectively. Six patients (cangrelor, n=3; placebo=3) experienced access site–related minor bleeding; there were no major bleedings and no need for transfusion.
| Variable | Cangrelor (n=25) | Placebo (n=25) |
|---|---|---|
| Age, y | 60 (11) | 60 (10) |
| Male, n (%) | 17 (68) | 16 (64) |
| Race, n (%) | ||
| White | 20 (80) | 13 (52) |
| Black | 5 (20) | 9 (36) |
| Hispanic | 0 (0) | 3 (12) |
| BMI, kg/m2 | 31 (9) | 32 (7) |
| Diabetes mellitus, n (%) | 10 (40) | 8 (33) |
| Smoking, n (%) | 13 (52) | 9 (36) |
| Hypertension, n (%) | 19 (76) | 18 (72) |
| Hyperlipidemia, n (%) | 13 (52) | 11 (44) |
| PAD, n (%) | 1 (4) | 1 (4) |
| Previous PCI, n (%) | 7 (28) | 3 (12) |
| Previous MI, n (%) | 4 (16) | 4 (16) |
| Previous CABG, n (%) | 1 (4) | 1 (4) |
| Previous stroke, n (%) | 1 (4) | 2 (8) |
| Creatinine, mg/dL | 0.9 (0.2) | 1.1 (0.7) |
| CrCl, mL/min | 114 (51) | 105 (45) |
| Platelet count, 103/mL* | 231 (63) | 248 (72) |
| Hematocrit, % | 42.2 (5.2) | 39.6 (8·6) |
| Hemoglobin, g/dL | 14.2 (1.8) | 13.9 (1·9) |
| Medications, n (%)*† | ||
| Aspirin | 25 (100) | 25 (100) |
| UFH | 25 (100) | 25 (100) |
| Bivalirudin | 0 (0) | 1 (4) |
| GPI | 1 (4) | 5 (20) |
| Ondansetron | 10 (40) | 13 (52) |
| Morphine | 7 (28) | 8 (32) |
| Time from bolus to end of PCI, min | 39 (18–51) | 33 (26–60) |
| Location of MI, n (%) | ||
| Anterior | 9 (36) | 11 (44) |
| Inferior | 14 (56) | 13 (52) |
| Lateral | 2 (8) | 1 (4) |
| Radial access, n (%) | 20 (80) | 20 (80) |
| Multivessel PCI, n (%) | 2 (8) | 2 (8) |
| TIMI flow before PCI, n (%) | ||
| 0 | 17 (68) | 13 (52) |
| 1 | 3 (12) | 7 (28) |
| 2 | 4 (16) | 4 (16) |
| 3 | 1 (4) | 1 (4) |
| TIMI flow after PCI, n (%) | ||
| 1–2 | 2 (8) | 3 (12) |
| 3 | 23 (92) | 22 (88) |
Data are mean (SD), median (interquartile range), or number (percent). There are no significant differences between groups in baseline characteristics. In the pharmacodynamic population, baseline characteristics were similar between the 2 groups, with the exception of race (P=0.025).
BMI indicates body mass index; CABG, coronary artery bypass graft; CrCl, creatinine clearance; GPI, glycoprotein IIb/IIIa inhibitor; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction; and UFH, unfractionated heparin.
*
Medications include those administered between hospital presentation and end of study.
†
All patients received fentanyl at the time of primary PCI as per local standard of care.
PD Findings
At baseline, there were no differences in PRU between groups. PRU levels were significantly lower in patients randomized to cangrelor compared with those randomized to placebo as early as 5 minutes after bolus (P<0.001; Figure 3). PRU levels at 30 minutes (primary end point) were significantly lower with cangrelor compared with placebo (63 [32–93] versus 214 [183–245]; mean difference, 152; 95% CI, 108–195; P<0.001; primary end point). PRU levels remained significantly lower in the cangrelor arm compared with the placebo arm until the end of the 2-hour infusion.
In the placebo arm, PRU levels reduced over time, with significant differences compared with baseline observed only 1 hour after drug administration (P<0.001), which became more marked after 2 hours (P<0.001). After discontinuation of drug infusion, in the cangrelor arm, there was an increase in PRU levels with significant differences at 1 hour (P=0.001) and 2 hours (P=0.027) after infusion compared with the end of infusion (2 hours after bolus). In the placebo arm, PRU levels continued to decline at 1 hour (P=0.059) and 2 hours (P=0.007) after infusion (Figure 3). PRU levels were similar at 1 and 2 hours after discontinuation of drug infusion (ie, at 3 and 4 hours after bolus) in each treatment arm. There were no differences in PRU levels between the 2 treatment arms after discontinuation of drug infusion, ruling out a DDI when cangrelor and ticagrelor are concomitantly administered (Figure 3). Parallel findings were observed during and after discontinuation of cangrelor/placebo infusion when platelet reactivity was measured by PRI (Figure 4). PRU and PRI levels during the overall time course were significantly lower in the cangrelor arm compared with the placebo arm (P<0.001 for both). Individual patient data on PRU and PRI distribution over time are illustrated in Figures I and II in the online-only Data Supplement. A total of 30% of patients received morphine before P-PCI, without significant differences between groups. An interaction analysis did not show any treatment-by-morphine interaction on the primary end point (P for interaction=0.586), as well as on any other time point.
An analysis of HPR status according to PRU showed that after bolus and during the entire duration of cangrelor infusion, rates of HPR were significantly lower with cangrelor compared with placebo (Figure 5 and Table I in the online-only Data Supplement). In particular, there were no patients with HPR during cangrelor infusion, whereas HPR status was reduced over time in the placebo arm but was still present in more than one-half of the patients at the end of PCI and in one-third of patients at the end of placebo infusion (ie, 2 hours after ticagrelor LD). After discontinuation of drug infusion, which corresponded to an increase and decrease in PRU in the cangrelor and placebo arms, respectively, rates of HPR were overall low and similar between groups. The latter observations are in line with the lack of a DDI between cangrelor and ticagrelor. Although HPR rates were higher when defined by PRI than those observed with the use of PRU, they showed parallel findings, with rates significantly lower with cangrelor compared with placebo during drug infusion and similar rates after discontinuation of drug infusion (Figure 5 and Table I in the online-only Data Supplement).
Discussion
CANTIC is the first randomized study to assess the comparative PD effects of cangrelor versus placebo in patients concomitantly treated with a crushed formulation of ticagrelor in patients with STEMI undergoing P-PCI. The key findings of the study are as follows: (1) The addition of cangrelor leads to prompter and more potent platelet inhibitory effects compared with crushed ticagrelor alone, with significant differences observed as early as 5 minutes after bolus administration; (2) treatment with cangrelor maintained significantly lower levels of platelet reactivity compared with crushed ticagrelor alone at 30 minutes (primary end point) and until the end of its 2-hour infusion; (3) compared with placebo, cangrelor was associated with significantly reduced rates of HPR on a background of crushed ticagrelor therapy; and (4) levels of platelet reactivity and HPR rates were similar between the randomized treatment arms after discontinuation of cangrelor/placebo infusion, ruling out a DDI when ticagrelor is concomitantly administered with cangrelor. Consistent findings were shown with 2 different platelet function assays, strengthening the validity of our study conclusions. Overall, these observations support the use of cangrelor in patients undergoing P-PCI as a strategy to achieve prompt and potent P2Y12 inhibitory effects and to bridge the gap in platelet inhibition associated with the use of ticagrelor, which can be administered concomitantly with cangrelor without evidence of DDI.
Antithrombotic therapy plays a key role in patients with STEMI undergoing P-PCI.1 Practice guidelines recommend the preferential use of the new-generation oral P2Y12 inhibitors prasugrel and ticagrelor in this setting given their more favorable net clinical benefit over clopidogrel.2 However, PD studies have consistently shown a delay in their onset of effects in P-PCI, exposing patients to an increased risk of early thrombotic complications.3–8 Such delay in antiplatelet effect is attributed to the reduced drug absorption that occurs in STEMI as a result of a multitude of factors, including impaired gastrointestinal motility and morphine use.1 Although crushing oral P2Y12 inhibitors has been suggested as a way to improve absorption and to achieve faster effects, with this strategy, up to one-third of patients persist with HPR, a well-established marker of thrombotic complications, within the first 2 hours after an LD administration, underscoring the need for prompter, more effective strategies to bridge this gap in platelet inhibition.7,8
Currently, 2 intravenous platelet inhibitors are available for clinical use: GPI and cangrelor.19 Prior PD investigations have shown GPI to represent an effective strategy to bridge the gap in platelet inhibition in patients undergoing P-PCI.20 However, the increased risk of bleeding associated with GPI and the growing awareness of the prognostic implications, including increased mortality, associated with bleeding complications have led to their reduced use in clinical practice.21 Cangrelor is a direct-acting P2Y12 inhibitor with fast onset and offset of action.9,22 Cangrelor was approved for clinical use on the basis of the results of the CHAMPION (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) PHOENIX trial, in which cangrelor significantly reduced ischemic events, including stent thrombosis, with no significant increase in severe bleeding.10 In the CHAMPION program, 11.6% of patients underwent P-PCI, and in this setting, cangrelor showed findings consistent with the overall trial results.11 However, cangrelor was tested against clopidogrel, which is not the preferred oral P2Y12 inhibitor in P-PCI, and the clinical outcomes associated with cangrelor in patients treated with prasugrel or ticagrelor are currently unknown.2,23,24 Moreover, there are limited data on the PD profile of cangrelor in patients undergoing P-PCI treated with either prasugrel or ticagrelor.
The present investigation supports that, in patients undergoing P-PCI, cangrelor is an effective strategy to bridge the gap in platelet inhibitory effects that occurs even with the use of crushed ticagrelor. Our study findings are in line with a smaller PD study conducted in patients with STEMI receiving whole tablets of ticagrelor.25 They also are consistent with data from observational cohorts of smaller ex vivo PD studies of patients undergoing P-PCI and patients after out-of-hospital cardiac arrest, as well in vitro or ex vivo investigations conducted in stable patients showing cangrelor to be associated with enhanced platelet inhibition when used on top of ticagrelor.18,26–28 Our study showed that, in the placebo arm, levels of platelet reactivity and the prevalence of HPR were still relatively high at the end of P-PCI and even up to 2 hours after drug administration. This may also explain the trend toward the higher prevalence of patients requiring bailout GPI in the placebo arm observed in our investigation. The increased rate of bailout GPI use is in line with observations in the placebo arm of the CHAMPION program; these patients also experienced worse outcomes.29–31
In patients treated with cangrelor, questions have emerged about the potential for DDI during the transition to oral P2Y12 inhibitors. In fact, cangrelor is associated with high levels of receptor occupancy, impeding binding of other agents.12,13 Therefore, the ability of an oral P2Y12 inhibitor to bind with the receptor depends largely on its bioavailability (ie, drug half-life) after discontinuation of cangrelor infusion.12,13 Because of the short half-life of their active metabolite, thienopyridines are recommended to be administered at the end of cangrelor infusion to avoid a DDI.12,13 Although a DDI has not been shown with ticagrelor, likely because of its longer bioavailability compared with the active metabolites of thienopyiridines, the data to support this derive from a small low-risk patient cohort not in the setting of PCI and from nonrandomized, single-center observational series.14,15 Accordingly, although the US Food and Drug Administration allows ticagrelor to be administered any time during cangrelor infusion, the European Medical Agency recommends that, similar to thienopyridines, ticagrelor be administered at the end of cangrelor infusion (alternatively, ticagrelor may be administered up to 30 minutes before the end of the infusion).23,24 CANTIC is the first study conducted in high-risk PCI, the design of which allowed exploration for a DDI between cangrelor and ticagrelor. In particular, there were no differences in levels of platelet reactivity and HPR rates between the treatment groups up to 2 hours after completion of cangrelor/placebo infusion, which largely rules out a DDI. Levels of platelet reactivity and HPR rates observed in the placebo arm were consistent with those observed in other studies of crushed formulations of oral P2Y12 inhibitors and lower than those observed with standard tablets.7,8 Thus, our data do not diminish the value of crushing tablets, which should be a strategy to consider in P-PCI to allow faster drug absorption so that this is systemically available after washout of cangrelor effects, allowing a smoother transition between therapies. However, the observation that some patients persist with HPR at 2 hours after a crushed LD of ticagrelor (with higher HPR rates with whole tablets even beyond 2 hours from drug administration) also makes it reasonable to maintain cangrelor infusion for up to 4 hours in patients undergoing P-PCI, which is line with the CHAMPION trial program, as reflected in the product label and expert consensus recommendations.10,11,13,23,24,32
Study Limitations
This study was not powered to assess the safety or efficacy of cangrelor in patients undergoing P-PCI; thus, any of the clinical findings of our study need to be interpreted with caution. However, our data are the best evidence on the effects of cangrelor in patients undergoing P-PCI receiving crushed ticagrelor and support its role as a strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y12 inhibitors in this clinical setting. Similarly, the numerically higher rate of bailout GPI use in the placebo arm needs to be interpreted with caution. However, this finding is in line with observations from the CHAMPION clinical trial program, which, like our study, was a double-blind and placebo-controlled trial limiting any confounders related to the operator’s decision to use bailout GPI.29,30 Although our study did not show any interaction between morphine use and PD findings, it is important to note that our study was not designed for this analysis. Moreover, all patients were also treated per standard of care with fentanyl, which is known to also interfere with the absorption of oral P2Y12 inhibitors,33 limiting the possibility of unraveling a potential effect induced by morphine. It may be argued that there was a greater magnitude of variability in platelet reactivity when assessed as defined by PRI compared with PRU. This in turn translated into higher rates of HPR defined by PRI than those observed with the use of PRU. However, these PD observations are consistent with prior studies and likely inherent to the vasodilator-stimulated phosphoprotein methodology, suggesting the need to consider a different HPR cutoff when PRI levels are considered.5,7,16,17 Our data cannot be extrapolated to patients in cardiogenic shock or those requiring a nasogastric tube. In fact, these patients, although attractive for the use of cangrelor, as already frequently occurs in clinical practice,34 were excluded from our study because they would have introduced heterogeneity to our study population, potentially interfering with our PD assessment of ticagrelor effects. Ultimately, assessment of the systemic levels of cangrelor and ticagrelor would have provided additional insights into the lack of DDI identified from PD data.
Conclusions
In patients undergoing P-PCI, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y12 inhibition induced by ticagrelor. Ticagrelor can be administered as a crushed formulation concomitantly with cangrelor without any apparent DDI. The clinical implications of these PD findings warrant investigation in an adequately powered clinical trial.
Acknowledgments
D.J.A. was the principal investigator for the study. F.F., F.R., and D.J.A. designed the study protocol and drafted the manuscript. F.F., F.R., and L.B. designed the statistical analyses and analyzed the data. D.J.A., A.R., M.F., M.B., M.A., Z.S., A.N., G.S., R.S., M.K., A.P., S.S., D.S., M.M.Z., and T.A.B. were involved in patient recruitment. D.J.A., F.F., F.R., A.P., S.S., D.S., M.M.Z., and T.A.B. critically revised the manuscript for important intellectual content. All authors approved the final manuscript.
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© 2019 American Heart Association, Inc.
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Received: 8 October 2018
Accepted: 4 December 2018
Published online: 11 January 2019
Published in print: 2 April 2019
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Dr Franchi reports receiving payments as an individual for consulting fee or honorarium from AstraZeneca and Sanofi. Dr Rollini reports receiving payments as an individual for consulting fee or honorarium from Chiesi. Dr Angiolillo reports receiving payments as an individual for the following: consulting fee or honorarium from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; and participation in review activities from CeloNova and St. Jude Medical; as well as institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, and Renal Guard Solutions. The other authors report no conflicts.
Sources of Funding
The present study was funded by an investigator-initiated grant from Chiesi. Chiesi had no role in study design conception, conduct of the study, or decision to publish these results.
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- Cangrelor versus crushed ticagrelor in patients with acute myocardial infarction and cardiogenic shock: rationale and design of the randomised, double-blind DAPT-SHOCK-AMI trial, EuroIntervention, 20, 20, (e1309-e1318), (2024).https://doi.org/10.4244/EIJ-D-24-00203
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